A Population-Based Study of the Long-Term Risk of Infections Associated With Hospitalization in Childhood Cancer Survivors.

2023

364-372

01/2023

1527-7755

PURPOSE: Infections pose a significant risk during therapy for childhood cancer. However, little is known about the risk of infection in long-term survivors of childhood cancer.

METHODS: We performed a retrospective observational study of children and adolescents born in Washington State diagnosed with cancer before age 20 years and who survived at least 5 years after diagnosis. Survivors were categorized as having a hematologic or nonhematologic malignancy and were matched to individuals without cancer in the state birth records by birth year and sex with a comparator:survivor ratio of 10:1. The primary outcome was incidence of any infection associated with a hospitalization using diagnostic codes from state hospital discharge records. Incidence was reported as a rate (IR) per 1,000 person-years. Multivariate Poisson regression was used to calculate incidence rate ratios (IRR) for cancer survivors versus comparators.

RESULTS: On the basis of 382 infection events among 3,152 survivors and 771 events among 31,519 comparators, the IR of all hospitalized infections starting 5 years after cancer diagnosis was 12.6 (95% CI, 11.4 to 13.9) and 2.4 (95% CI, 2.3 to 2.6), respectively, with an IRR 5.1 (95% CI, 4.5 to 5.8). The survivor IR during the 5- to 10-year (18.1, 95% CI, 15.9 to 20.5) and > 10-year postcancer diagnosis (8.3, 95% CI, 7.0 to 9.7) periods remained greater than comparison group IRs for the same time periods (2.3, 95% CI, 2.1 to 2.6 and 2.5, 95% CI, 2.3 to 2.8, respectively). When potentially vaccine-preventable infections were evaluated, survivors had a greater risk of infection relative to comparators (IRR, 13.1; 95% CI, 7.2 to 23.9).

CONCLUSION: Infectious complications continue to affect survivors of childhood cancer many years after initial diagnosis. Future studies are needed to better understand immune reconstitution to determine specific factors that may mitigate this risk.

10.1200/JCO.22.00230

J Clin Oncol

35878085

Prospective Evaluation of the Fungitell® (1→3) Beta-D-Glucan Assay as a Diagnostic Tool for Invasive Fungal Disease in Pediatric Allogeneic Hematopoietic Cell Transplantation: A Report from the Children's Oncology Group.

2023

e14399

02/2023

1399-3046

BACKGROUND: Invasive fungal disease (IFD) is a major source of morbidity and mortality for hematopoietic cell transplant (HCT) recipients. Non-invasive biomarkers, such as the beta-D-glucan assay, may improve the diagnosis of IFD. The objective was to define the utility of surveillance testing using Fungitell® beta-D-glucan (BDG) assay in children receiving antifungal prophylaxis in the immediate post-HCT period.

METHODS: Weekly surveillance blood testing with the Fungitell® BDG assay was performed during the early post-HCT period in the context of a randomized trial of children, adolescents, and young adults undergoing allogeneic HCT allocated to triazole or caspofungin prophylaxis. Positivity was defined at the manufacturer cutoff of 80 pg/ml. IFD was adjudicated using blinded central reviewers. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the Fungitell® BDG assay for the outcome of proven or probable IFD.

RESULTS: A total of 51 patients (out of 290 patients in the parent trial) contributed blood specimens. In total, 278 specimens were evaluated. Specificity was 80.8% (95% confidence interval [CI]: 75.6%-85.3%), and NPV was over 99% (95% CI: 86.8%-99.9%). However, there were no true positive results, resulting in sensitivity of 0% (95% CI: 0.0%-84.2%) and PPV of 0% (95% CI: 0.0%-6.7%).

CONCLUSIONS: Fungitell® BDG screening is of limited utility in diagnosing IFD in the post-HCT period, mainly due to high false-positive rates. Fungitell® BDG surveillance testing should not be performed in children during the early post-HCT period while receiving antifungal prophylaxis as the pretest probability for IFD is low.

10.1111/petr.14399

Pediatr Transplant

36299233

A Population-Based Study of the Long-Term Risk of Infections Associated With Hospitalization in Childhood Cancer Survivors.

2022

JCO2200230

07/2022

1527-7755

PURPOSE: Infections pose a significant risk during therapy for childhood cancer. However, little is known about the risk of infection in long-term survivors of childhood cancer.

METHODS: We performed a retrospective observational study of children and adolescents born in Washington State diagnosed with cancer before age 20 years and who survived at least 5 years after diagnosis. Survivors were categorized as having a hematologic or nonhematologic malignancy and were matched to individuals without cancer in the state birth records by birth year and sex with a comparator:survivor ratio of 10:1. The primary outcome was incidence of any infection associated with a hospitalization using diagnostic codes from state hospital discharge records. Incidence was reported as a rate (IR) per 1,000 person-years. Multivariate Poisson regression was used to calculate incidence rate ratios (IRR) for cancer survivors versus comparators.

RESULTS: On the basis of 382 infection events among 3,152 survivors and 771 events among 31,519 comparators, the IR of all hospitalized infections starting 5 years after cancer diagnosis was 12.6 (95% CI, 11.4 to 13.9) and 2.4 (95% CI, 2.3 to 2.6), respectively, with an IRR 5.1 (95% CI, 4.5 to 5.8). The survivor IR during the 5- to 10-year (18.1, 95% CI, 15.9 to 20.5) and > 10-year postcancer diagnosis (8.3, 95% CI, 7.0 to 9.7) periods remained greater than comparison group IRs for the same time periods (2.3, 95% CI, 2.1 to 2.6 and 2.5, 95% CI, 2.3 to 2.8, respectively). When potentially vaccine-preventable infections were evaluated, survivors had a greater risk of infection relative to comparators (IRR, 13.1; 95% CI, 7.2 to 23.9).

CONCLUSION: Infectious complications continue to affect survivors of childhood cancer many years after initial diagnosis. Future studies are needed to better understand immune reconstitution to determine specific factors that may mitigate this risk.

10.1200/JCO.22.00230

J Clin Oncol

35878085

Prospective Evaluation of Galactomannan and (1→3) β-d-Glucan Assays as Diagnostic Tools for Invasive Fungal Disease in Children, Adolescents, and Young Adults With Acute Myeloid Leukemia Receiving Fungal Prophylaxis.

2021

2021 Jun 26

2048-7207

BACKGROUND: Patients receiving chemotherapy for acute myeloid leukemia (AML) are at high risk for invasive fungal disease (IFD). Diagnosis of IFD is challenging, leading to interest in fungal biomarkers. The objective was to define the utility of surveillance testing with Platelia Aspergillus galactomannan (GM) enzyme immunoassay (EIA) and Fungitell β-d-glucan (BDG) assay in children with AML receiving antifungal prophylaxis.

METHODS: Twice-weekly surveillance blood testing with GM EIA and BDG assay was performed during periods of neutropenia in the context of a randomized trial of children, adolescents, and young adults with AML allocated to fluconazole or caspofungin prophylaxis. Proven or probable IFD was adjudicated using blinded central reviewers. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for Platelia and Fungitell assays alone and in combination for the outcomes of proven and probable invasive aspergillosis (IA) or invasive candidiasis (IC).

RESULTS: Among 471 patients enrolled, 425 participants (209 fluconazole and 216 caspofungin) contributed ≥1 blood specimen. In total, 6103 specimens were evaluated, with a median of 15 specimens per patient (range 1-43). The NPV was >99% for GM EIA and BDG assay alone and in combination. However, there were no true positive results, resulting in sensitivity and PPV for each assay of 0%.

CONCLUSIONS: The GM EIA and the BDG assay alone or in combination were not successful at detecting IA or IC during periods of neutropenia in children, adolescents, and young adults with AML receiving antifungal prophylaxis. Utilization of these assays for surveillance in this clinical setting should be discouraged.

10.1093/jpids/piab036

J Pediatric Infect Dis Soc

34173659

Challenges and Barriers to Adverse Event Reporting in Clinical Trials: A Children's Oncology Group Report.

2021

2021 Sep 23

1549-8425

<p><strong>OBJECTIVE: </strong>Adverse event (AE) reporting is crucial for determining safety of trials. Adverse events are captured manually by clinical research associates (CRAs) and research nurses (RNs), and prior studies show underreporting. It is necessary to understand AE reporting training, processes, and institution-level differences to improve AE capture.</p>

<p><strong>METHODS: </strong>A 26-item questionnaire regarding AE reporting training, identification, tracking, and challenges was distributed to all Children's Oncology Group (COG) CRAs and RNs from February 15 to March 11, 2019, regardless of if they report AEs based on limitations of COG rosters. Results were tabulated. Institutions were grouped by self-reported full-time equivalents and compared using χ2 tests.</p>

<p><strong>RESULTS: </strong>Of 1315 CRAs and 2703 RNs surveyed, 509 (12.7%) responded. Of those, 369 (64.9%) representing 71.8% of COG institutions report AEs. Only data from respondents who report AEs were collected and analyzed. There was a range in AE training; COG training modules were most common (79.7%). There was wide variability in AE ascertainment; only 51.2% use standardized approaches at their site. There was no standard AE tracking method; larger sites more commonly use spreadsheets (P = 0.002) and smaller sites more commonly use paper (P = 0.028). The greatest AE reporting challenges were differences between protocols (70%) and between AE definitions and documentation (53%). Half of the respondents endorsed 6 of 13 proposed tools for improving reporting including online AE reporting modules (75.3%), tip sheets for interpreting Common Terminology Criteria for Adverse Events definitions (67.5%), and standardized AE tracking forms (66.9%). Only half of the respondents reported that all colleagues at their site followed the same AE reporting practices, and there was no dominant AE tracking approach across the respondents.</p>

<p><strong>DISCUSSION: </strong>There is wide variability in AE reporting training and practices. Numerous challenges exist, including differences between trials, challenges in interpreting AE definitions, and engaging clinicians.</p>

<p><strong>CONCLUSIONS: </strong>Respondents are eager for additional central resources. These results provide a roadmap for areas of potential improvement.</p>

10.1097/PTS.0000000000000911

J Patient Saf

34570002

Veno-occlusive disease after high-dose busulfan-melphalan in neuroblastoma.

2020

531-537

2020 03

1476-5365

<p>Survival for high-risk neuroblastoma patients is still suboptimal. Although stem cell transplantation (SCT) is used, there is no consensus as to which conditioning regimen has the greatest efficacy and fewest toxicities. We assessed the incidence of and risk for hepatic veno-occlusive disease (VOD) for neuroblastoma patients who underwent autologous SCT with busulfan and melphalan (BuMel) at eight centers following Children's Oncology Group (COG)-based induction chemotherapy. Data regarding the patients, SCT characteristics, busulfan steady-state concentrations, incidence of VOD, and survival were evaluated. VOD was defined using the modified Seattle criteria. Possible factors associated with VOD (age, busulfan-pharmacokinetic parameters, history of hepatic dysfunction, and day of neutrophil engraftment) were evaluated. Seventy five patients were included and 23 children (31%) developed VOD at a median of 19 days after SCT (range 14-27 days). VOD was the cause of death in 4 patients (5%). In a multivariable analysis, young age (OR 1.7 (95% CI: 1.16-2.56; p = 0.012))&nbsp;and early day of neutrophil engraftment (OR 1.4 (95% CI: 1.08-2.14; p = 0.041)&nbsp;were associated with the development of VOD. Initial or cumulative busulfan steady-state concentration were not associated with VOD. We found that despite the use of intravenous busulfan with adjusted serum levels, the incidence of VOD remains high in pediatric neuroblastoma patients.</p>

10.1038/s41409-018-0298-y

Bone Marrow Transplant

30181580

A Randomized Trial of Caspofungin vs Triazoles Prophylaxis for Invasive Fungal Disease in Pediatric Allogeneic Hematopoietic Cell Transplant.

2020

2020 Nov 02

2048-7207

<p><strong>BACKGROUND: </strong>Children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) are at high risk for invasive fungal disease (IFD).</p>

<p><strong>METHODS: </strong>This multicenter, randomized, open-label trial planned to enroll 560 children and adolescents (3 months to &lt;21 years) undergoing allogeneic HCT between April 2013 and September 2016. Eligible patients were randomly assigned to antifungal prophylaxis with caspofungin or a center-specific comparator triazole (fluconazole or voriconazole). Prophylaxis was administered from day 0 of HCT to day 42 or discharge. The primary outcome was proven or probable IFD at day 42 as adjudicated by blinded central review. Exploratory analysis stratified this evaluation by comparator triazole.</p>

<p><strong>RESULTS: </strong>A planned futility analysis demonstrated a low rate of IFD in the comparator triazole arm, so the trial was closed early. A total of 290 eligible patients, with a median age of 9.5 years (range 0.3-20.7), were randomized to caspofungin (n = 144) or a triazole (n = 146; fluconazole, n = 100; voriconazole, n = 46). The day 42 cumulative incidence of proven or probable IFD was 1.4% (95% confidence interval [CI], 0.3%-5.4%) in the caspofungin group vs 1.4% (95% CI, 0.4%-5.5%) in the triazole group (P = .99, log-rank test). When stratified by specific triazole, there was no significant difference in proven or probable IFD at day 42 between caspofungin vs fluconazole (1.0%, 95% CI, 0.1%-6.9%, P = .78) or caspofungin vs voriconazole (2.3%, 95% CI, 0.3%-15.1%, P = .69).</p>

<p><strong>CONCLUSIONS: </strong>In pediatric HCT patients, prophylaxis with caspofungin did not significantly reduce the cumulative incidence of early proven or probable IFD compared with triazoles. Future efforts to decrease IFD-related morbidity and mortality should focus on later periods of risk.</p>

<p><strong>TRIAL REGISTRATION: </strong>NCT01503515.</p>

10.1093/jpids/piaa119

J Pediatric Infect Dis Soc

33136159

Chlorhexidine gluconate bathing in children with cancer or those undergoing hematopoietic stem cell transplantation: A double-blinded randomized controlled trial from the Children's Oncology Group.

2020

2020 Oct 20

1097-0142

<p><strong>BACKGROUND: </strong>To the authors' knowledge, information regarding whether daily bathing with chlorhexidine gluconate (CHG) reduces central line-associated bloodstream infection (CLABSI) in pediatric oncology patients and those undergoing hematopoietic stem cell transplantation (HCT) is limited.</p>

<p><strong>METHODS: </strong>In the current multicenter, randomized, double-blind, placebo-controlled trial, patients aged ≥2 months and &lt;22 years with cancer or those undergoing allogeneic HCT were randomized 1:1 to once-daily bathing with 2% CHG-impregnated cloths or control cloths for 90 days. The primary outcome was CLABSI. Secondary endpoints included total positive blood cultures, acquisition of resistant organisms, and acquisition of cutaneous staphylococcal isolates with an elevated CHG mean inhibitory concentration.</p>

<p><strong>RESULTS: </strong>The study was stopped early because of poor accrual. Among the 177 enrolled patients, 174 were considered as evaluable (88 were randomized to the CHG group and 86 were randomized to the control group). The rate of CLABSI per 1000 central line days in the CHG group was 5.44 versus 3.10 in the control group (risk difference, 2.37; 95% confidence interval, 0.05-4.69 [P = .049]). Post hoc conditional power analysis demonstrated a 0.2% chance that the results would have favored CHG had the study fully enrolled. The rate of total positive blood cultures did not differ between groups (risk difference, 2.37; 95% confidence interval, -0.41 to 5.14 [P = .078]). The number of patients demonstrating the new acquisition of resistant organisms did not differ between groups (P = .54). Patients in the CHG group were found to be more likely to acquire cutaneous staphylococcal isolates with an elevated CHG mean inhibitory concentration (P = .032).</p>

<p><strong>CONCLUSIONS: </strong>The data from the current study do not support the use of routine CHG bathing in children with cancer or those undergoing allogeneic HCT.</p>

10.1002/cncr.33271

Cancer

33079403

Effect of Caspofungin vs Fluconazole Prophylaxis on Invasive Fungal Disease Among Children and Young Adults With Acute Myeloid Leukemia: A Randomized Clinical Trial.

2019

1673-1681

2019 11 05

1538-3598

<p><strong>Importance: </strong>Children, adolescents, and young adults with acute myeloid leukemia are at high risk of life-threatening invasive fungal disease with both yeasts and molds.</p>

<p><strong>Objective: </strong>To compare the efficacy of caspofungin vs fluconazole prophylaxis against proven or probable invasive fungal disease and invasive aspergillosis during neutropenia following acute myeloid leukemia chemotherapy.</p>

<p><strong>Design, Setting, and Participants: </strong>This multicenter, randomized, open-label, clinical trial enrolled patients aged 3 months to 30 years with newly diagnosed de novo, relapsed, or secondary acute myeloid leukemia being treated at 115 US and Canadian institutions (April 2011-November 2016; last follow-up June 30, 2018).</p>

<p><strong>Interventions: </strong>Participants were randomly assigned during the first chemotherapy cycle to prophylaxis with caspofungin (n = 257) or fluconazole (n = 260). Prophylaxis was administered during the neutropenic period following each chemotherapy cycle.</p>

<p><strong>Main Outcomes and Measures: </strong>The primary outcome was proven or probable invasive fungal disease as adjudicated by blinded central review. Secondary outcomes were invasive aspergillosis, empirical antifungal therapy, and overall survival.</p>

<p><strong>Results: </strong>The second interim efficacy analysis and an unplanned futility analysis based on 394 patients appeared to have suggested futility, so the study was closed to accrual. Among the 517 participants who were randomized (median age, 9 years [range, 0-26 years]; 44% female), 508 (98%) completed the trial. The 23 proven or probable invasive fungal disease events (6 caspofungin vs 17 fluconazole) included 14 molds, 7 yeasts, and 2 fungi not further categorized. The 5-month cumulative incidence of proven or probable invasive fungal disease was 3.1% (95% CI, 1.3%-7.0%) in the caspofungin group vs 7.2% (95% CI, 4.4%-11.8%) in the fluconazole group (overall P = .03 by log-rank test) and for cumulative incidence of proven or probable invasive aspergillosis was 0.5% (95% CI, 0.1%-3.5%) with caspofungin vs 3.1% (95% CI, 1.4%-6.9%) with fluconazole (overall P = .046 by log-rank test). No statistically significant differences in empirical antifungal therapy (71.9% caspofungin vs 69.5% fluconazole, overall P = .78 by log-rank test) or 2-year overall survival (68.8% caspofungin vs 70.8% fluconazole, overall P = .66 by log-rank test) were observed. The most common toxicities were hypokalemia (22 caspofungin vs 13 fluconazole), respiratory failure (6 caspofungin vs 9 fluconazole), and elevated alanine transaminase (4 caspofungin vs 8 fluconazole).</p>

<p><strong>Conclusions and Relevance: </strong>Among children, adolescents, and young adults with acute myeloid leukemia, prophylaxis with caspofungin compared with fluconazole resulted in significantly lower incidence of invasive fungal disease. The findings suggest that caspofungin may be considered for prophylaxis against invasive fungal disease, although study interpretation is limited by early termination due to an unplanned interim analysis that appeared to have suggested futility.</p>

<p><strong>Trial Registration: </strong>ClinicalTrials.gov Identifier: NCT01307579.</p>

10.1001/jama.2019.15702

JAMA

31688884

Effect of Levofloxacin Prophylaxis on Bacteremia in Children With Acute Leukemia or Undergoing Hematopoietic Stem Cell Transplantation: A Randomized Clinical Trial.

2018

995-1004

2018 Sep 11

1538-3598

<p><strong>Importance: </strong>Bacteremia causes considerable morbidity among children with acute leukemia and those undergoing hematopoietic stem cell transplantation (HSCT). There are limited data on the effect of antibiotic prophylaxis in children.</p>

<p><strong>Objective: </strong>To determine the efficacy and risks of levofloxacin prophylaxis in children receiving intensive chemotherapy for acute leukemia or undergoing HSCT.</p>

<p><strong>Design, Setting, and Participants: </strong>In this multicenter, open-label, randomized trial, patients (6 months-21 years) receiving intensive chemotherapy were enrolled (September 2011-April 2016) in 2 separate groups-acute leukemia, consisting of acute myeloid leukemia or relapsed acute lymphoblastic leukemia, and HSCT recipients-at 76 centers in the United States and Canada, with follow-up completed September 2017.</p>

<p><strong>Interventions: </strong>Patients with acute leukemia were randomized to receive levofloxacin prophylaxis for 2 consecutive cycles of chemotherapy (n = 100) or no prophylaxis (n = 100). Those undergoing HSCT were randomized to receive levofloxacin prophylaxis during 1 HSCT procedure (n = 210) or no prophylaxis (n = 214).</p>

<p><strong>Main Outcomes and Measures: </strong>The primary outcome was the occurrence of bacteremia during 2 chemotherapy cycles (acute leukemia) or 1 transplant procedure (HSCT). Secondary outcomes included fever and neutropenia, severe infection, invasive fungal disease, Clostridium difficile-associated diarrhea, and musculoskeletal toxic effects.</p>

<p><strong>Results: </strong>A total of 624 patients, 200 with acute leukemia (median [interquartile range {IQR}] age, 11 years [6-15 years]; 46% female) and 424 undergoing HSCT (median [IQR] age, 7 years [3-14]; 38% female), were enrolled. Among 195 patients with acute leukemia, the likelihood of bacteremia was significantly lower in the levofloxacin prophylaxis group than in the control group (21.9% vs 43.4%; risk difference, 21.6%; 95% CI, 8.8%-34.4%, P = .001), whereas among 418 patients undergoing HSCT, the risk of bacteremia was not significantly lower in the levofloxacin prophylaxis group (11.0% vs 17.3%; risk difference, 6.3%; 95% CI, 0.3%-13.0%; P = .06). Fever and neutropenia were less common in the levofloxacin group (71.2% vs 82.1%; risk difference, 10.8%; 95% CI, 4.2%-17.5%; P = .002). There were no significant differences in severe infection (3.6% vs 5.9%; risk difference, 2.3%; 95% CI, -1.1% to 5.6%; P = .20), invasive fungal disease (2.9% vs 2.0%; risk difference, -1.0%; 95% CI, -3.4% to 1.5%, P = .41), C difficile-associated diarrhea (2.3% vs 5.2%; risk difference, 2.9%; 95% CI, -0.1% to 5.9%; P = .07), or musculoskeletal toxic effects at 2 months (11.4% vs 16.3%; risk difference, 4.8%; 95% CI, -1.6% to 11.2%; P = .15) or at 12 months (10.1% vs 14.4%; risk difference, 4.3%; 95% CI, -3.4% to 12.0%; P = .28) between the levofloxacin and control groups.</p>

<p><strong>Conclusions and Relevance: </strong>Among children with acute leukemia receiving intensive chemotherapy, receipt of levofloxacin prophylaxis compared with no prophylaxis resulted in a significant reduction in bacteremia. However, there was no significant reduction in bacteremia for levofloxacin prophylaxis among children undergoing HSCT.</p>

10.1001/jama.2018.12512

JAMA

30208456